The invention relates to an improved process for making 3-amino-2-chloro-4-methylpyridine, also known as CAPIC.
CAPIC is a key intermediate in the production of nevirapine, a non-nucleosidic reverse transcriptase inhibitor that has been established to be clinically useful for the treatment of infection by HIV-1. 
Syntheses of nevirapine from CAPIC have been described by Hargrave et al., in J. Med. Chem. 34, 2231 (1991) and U.S. Pat. No. 5,366,972, and by Schneider et al., in U.S. Pat. No. 5,569,760.
Several processes for preparing CAPIC have been described in the literature. It is believed that the earliest synthesis of CAPIC, depicted below in Scheme 1, is that of Chapman et al. (J. Chem Soc.Perkin Trans.1, (1980), 2398-2404). 
A closely related synthesis for CAPIC, depicted below in Scheme 2, has been described by Hargrave et al. (U.S. Pat. No. 5,366,972). 
As reported by Grozinger et al. (J. Heterocyclic Chem., 32, 259 (1995)), CAPIC has been synthesized in small laboratory batches by nitrating the readily available 2-amino-4-picoline or 2-hydroxy-4-picoline, as depicted below in Scheme 3. This procedure suffers from non-selective nitration at positions 3 and 5, as well as thermo-chemical hazards and potential for xe2x80x9crun-awayxe2x80x9d when carried out in large quantities. 
The drawbacks of the nitration-based process lead Grozinger to develop the two synthetic routes, which start from ethylacetoacetone and cyanacetamide, that are described in U.S. Pat. Nos. 5,668,287 and are depicted below in Schemes 4 and 5. Both of the latter two synthetic routs require the dichlorination of the intermediate 2,6-dihydroxy-2 and 6, subsequent de-chlorination and finally selective re-chorination, using chlorine gas, at position 2. The di-chlorination and dehalogenation, as well as the selective monochlorination at position 2 require special manufaturing equipment that is expensive and may not be readily available. 
Schneider (U.S. Pat. No. 5,686,618) has provided an alternative means for mono-chlorinating 3-amino-4-methylpyridine at position 2, using H2O2 in HCl, instead of chlorine gas.
Yet another synthesis, depicted below in Scheme 6, comprising the steps of chlorination of ethyl cyanoacetate, Michael addition with crotonaldehyde, cyclization, conversion to the amide and finally reduction to the amine has been described by Zhang et al. (Tetrahedron 51(48), 13177-13184 (1995)), who report that while the desired product was obtained, the Michael addition was slow and the cyclization low-yielding. 
A synthesis beginning with 2-chloro-3-aminopyridine has been disclosed by Nummy (U.S. Pat. No. 5,654,429). This is depicted below in Scheme 7. 
International Application WO 00/43365 describes the process for preparing CAPIC that is depicted below in Scheme 8. 
A closely related alternative, depicted below in Scheme 9, is disclosed in International Application PCT/US00/00261. 
Baldwin et al. (J. Org. Chem., 43, 2529 (1978)), reported a method for the preparation of 2-halonicotinic acid derivatives using xcex2,xcex3-unsaturated aldehyde equivalents as shown in Scheme 10. The procedure involves the initial Knovenagel condensation of an aldehyde or ketone with ethyl cyanoacetate or malonitrile followed by reaction with DMF acetal. The cyclization of the xcex2,xcex3-unsaturated aldehyde equivalent is carried out by treatment with HBr-acetic acid to give the 2-bromo adduct directly. Reaction yields with DMF acetal were in the 5 to 60% range, depending on the nature of the alkyl substituents. In several cases, the reaction of DMF acetal with the Knovenagel adduct led to dimer formation. Overall yields for the two step process varied from 3 to 35% depending on the nature of the substituents. 
Baldwin et al., supra., also used mixtures of acetals and enol ethers as xcex2,xcex3-unsaturated aldehyde equivalents to overcome the limitations associated with the use of DMF acetal in the preparation of 2-bromonicotinic acid derivatives (Scheme 11). Yields also tended to vary with this approach depending on the substitution pattern of Knovenagel adduct. Yields for the cyclization step ranged from 29 to 74% while overall yields for the two step process ranged from 15 to 40%. 
In summary, the methods that have been developed to date for the preparation of CAPIC and other related 4-alkylnicotinic acid derivatives suffer from excessive complexity, inefficiency and/or lack of regiocontrol. Of the approaches considered, Baldwin""s use of acetal/enol ether systems addresses the regioselectivity issues most effectively
In its most general aspect, the invention comprises an improved process for the preparation of 2-chloro-3-amino-4-methylpyridine (CAPIC) which comprises the following steps:
(a) reacting acetylacetaldehyde dimethyl acetal 
xe2x80x83with malononitrile 
xe2x80x83to yield a mixture of 4,4-dicyano-3-methyl-3-butenal dimethyl acetal and 1,1-dicyano-4-methoxy-2-methyl-1,3-butadiene 
(b) treating the mixture of 4,4-dicyano-3-methyl-3-butenal dimethyl acetal and 1,1-dicyano-4-methoxy-2-methyl-1,3-butadiene so produced with a strong acid and water, to yield 3-cyano-4-methyl-2-pyridone 
(c) treating the 3-cyano-4-methyl-2-pyridone so produced with a strong chlorinating agent, to yield 3-cyano-2-chloro-4-methylpyridine 
(d) treating the 3-cyano-2-chloro-4-methylpyridine produced in the preceding step with a strong acid and water, to yield 2-chloro-3-amido-4-methylpyridine 
(e) treating the 2-chloro-3-amido-4-methylpyridine produced in the preceding step with a strong base and a halide, to yield 2-chloro-3-amino-4-methylpyridine.
This general method is depicted below in Scheme 12. 
The intermediates 4,4-dicyano-3-methyl-3-butenal dimethyl acetal and 1,1-dicyano-4-methoxy-2-methyl-1,3-butadiene are believed to be novel, and constitute an aspect of the invention.
The first step of the above-described process is a Knovenagel condensation. This is carried out in an organic solvent at a temperature in the range between 0 and 50xc2x0 C. Acceptable solvents are, for example, aromatic hydrocarbons such as benzene, toluene or alkanols such as methanol, ethanol, propanols and other higher molecular weight alcohols. The preferred solvents are toluene and methanol. The preferred reaction temperature is 15 to 25xc2x0 C. The condensation is run in the presence of a small quantity of an ammonium salt catalyst. Preferred catalysts are heterocyclic ammonium salts. Most preferred is piperidinium acetate.
The product of the Knovenagel condensation is a mixture of 4,4-dicyano-3-methyl-3-butenal dimethyl acetal and 1,1-dicyano-4-methoxy-2-methyl-1,3-butadiene. These two compounds need not be separated, as they both are converted in the next step, which is an acid-catalyzed cyclization, to 3-cyano-4-methyl-2-pyridone. It is possible to conduct the cyclization simply by acidifying the initial reaction mixture, without isolation of the mixture of intermediates. However, it is preferred to first isolate the two intermediates from the other components of the crude Knovenagel reaction mixture. This is conveniently accomplished by washing the reaction mixture emanating from the condensation with water, to remove the basic catalyst, followed by evaporation, to remove the solvent (toluene or methanol).
While the crude reaction mixture can be carried forward to the next step after catalyst removal and concentration, it has been discovered that this crude product contains undesired byproducts that tend to be carried forward into subsequent reaction steps and reduce yields. Therefore it is desirable to remove these byproducts once the catalyst removal and concentration have been completed. The removal of these byproducts can be performed by simple distillation techniques, preferably by continuous short path distillation such as wiped or thin film evaporation. This technique is particularly effective for the removal of high boiling materials, which appears to be sufficient to obtain the observed yield improvements.
The acid-catalyzed cyclization is performed with a strong acid, such as, for example, concentrated and sulfuric acid. As the reaction is highly exothermic, it is best to introduce the mixture of 4,4-dicyano-3-methyl-3-butenal dimethyl acetal and 1,1-dicyano-4-methoxy-2-methyl-1,3-butadiene into the acid slowly, and with stirring, so that the temperature of the mixture does not rise above about 50xc2x0 C. After evolution of heat has substantially ceased, the reaction mixture is heated to between about 30 and 50xc2x0 C. preferably 50xc2x0 C. and held at that temperature for between about 1 and 3 hours, preferably about 1.5 hours, to complete the reaction. The reaction mixture is cooled to ambient temperature, water is added, and the intermediate product, 3-cyano-4-methyl-2-pyridone, is filtered off, washed with water and dried.
Next, the 3-cyano-4-methyl-2-pyridone so produced is treated with a strong chlorinating agent. Suitable chlorinating agents are SOCl2, POCl3 and PCl5. It is preferred to use POCl3 (10 parts)and PCl5(1 part). The reaction mixture is heated to reflux (approximately 115xc2x0 C.) and held under this condition for about two hours, or until the chlorination is essentially complete. The chlorinating agent is removed. For example, excess POCl3 may be removed by distillation. The reaction mixture is then cooled and water is added. The 2-chloro-3-cyano-4-methylpyridine is filtered from the aqueous mixture. The aqueous filtrate is extracted with an inert organic solvent such as chloroformn, methylene chloride, with methylene chloride being preferred in order to recover the residual 2-chloro-3-cyano-4-methylpyridine.
The 3-cyano intermediate is next converted to a 3-amido compound. This is accomplished by treating the cyano intermediate with a concentrated, aqueous strong acid, such as sulfuric acid. This is preferably done with stirring, at a temperature between about 70 and 110xc2x0 C. preferably at about 90xc2x0 C. The mixture was heated to between about 80 and 120xc2x0 C., preferably about 100xc2x0 C. and held at that temperature for three hours, or until further reaction ceases. The reaction mixture is then cooled to between about 70 and 110xc2x0 C. preferably about 90xc2x0 C. and water is added. The mixture is then cooled to between about 0 and 20xc2x0 C. preferably about 10xc2x0 C. and held at that temperature for about one hour. The solid product, 2-chloro-3-amido-4-methylpyridine, is isolated from the reaction mixture by filtration, washed with water and dried.
In the final step of the process, the 3-amido intermediate is converted to the 3-amino final product by adding it to a mixture of a strong base and a halogen. The base may be aqueous sodium carbonate or sodium hydroxide, preferably sodium hydroxide. The halogen may be chlorine or bromine, preferably bromine. The resulting reaction mixture is heated to between about 10 and 30xc2x0 C. preferably to about 22xc2x0 C. Water is then added to the reaction mixture followed by heating to between 60 and 80xc2x0 C. preferably to about 70xc2x0 C. for one additional hour. The reaction mixture is cooled to ambient temperature and extracted with an inert organic solvent, such as chloroform or methylene chloride, preferably methylene chloride. The organic solvent is removed by evaporation, to yield 2-chloro-3-amino-4-methylpyridine.